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Gene Discovery Offers Hope for Treating ER-positive Breast Cancer

Sep 29, 2015

Estrogen is an important female hormone that signals the breasts to form during puberty. It's a necessity for normal mammary gland development. Yet, in some cases, the hormone also helps abnormal breast cells to grow, giving rise to the most common subtype of breast cancer, called estrogen receptor-positive (ER-positive) disease. How and why this happens has long been investigated.

"One of the key questions that has eluded us for many years is how, at the molecular level within the breast cancer tumors, does estrogen drive cell proliferation," says Paraic Kenny, PhD, director of the oncology research laboratory at the Kabara Cancer Research Institute in Wisconsin. He's been working on an American Cancer Society-funded project to better understand how problems with estrogen signaling in the body drive breast cancer development. His research suggests that a gene switched on during puberty, called Amphiregulin, plays a critical role.

"Our American Cancer Society-supported research has allowed us to identify a new and very important mechanism that controls the cell proliferation in ER-positive breast cancer," says Kenny. "We have determined that Amphiregulin, a key growth factor, is required for the growth of ER-positive human breast cancer cell lines in mouse models."

What is Amphiregulin?

Amphiregulin is a gene required for normal breast development that is controlled by estrogen. It is also found at high levels in many ER-positive breast tumors. The gene releases a protein (also called Amphiregulin), which sticks to other proteins called receptors on the outside of breast cancer cells. These receptors act as an antenna, picking up signals that tell the cells to grow.

Kenny's team wanted to know what happened when they knocked out the gene in mice. "We see that breast cancer cells, in which we experimentally switched off Amphiregulin, have a failure in growth in the mouse. They grow much more slowly," he explains. "That basically confirmed our major hypothesis underlying our ACS-funded grant."

His team is now creating genetically engineered mouse models that lack the Amphiregulin gene and are combining those with mutations that frequently occur in human breast cancer to determine if breast tumors still occur. Kenny calls this "the most rigorous experimental test of the importance of Amphiregulin in breast cancer development."

Targeted Treatment, Fewer Side Effects

In prior research, Kenny determined how breast cancer cells released Amphiregulin. An enzyme that works like a pair of molecular scissors snips the gene's sequence in two. "That releases the signaling molecule that instructs the breast cancers to grow," he says. "After this happens, a little stub of Amphiregulin is left behind on the cell surface."

That foundational knowledge has allowed Kenny and colleagues to develop antibodies that selectively recognize the snipped (or "cleaved") form of Amphiregulin. He's now working on joining potent chemotherapies to the antibodies in hopes of creating a new therapeutic strategy for targeting breast tumors.

"Rather than having chemotherapy go to all the cells in the body and creating all sorts of damage like gastrointestinal toxicity, hair loss, and bone marrow suppression, we can concentrate the treatment in the vicinity of breast cancer cells and trick them to take up this chemotherapeutic," Kenny says.

Such targeted therapy may also benefit women with ER-positive cancer whose disease continues to spread despite hormonal therapies, like tamoxifen.

"About 30% of ER-positive tumors stop responding to these drugs, and we have some evidence that a subset of them continue to make Amphiregulin independently of estrogen," says Kenny. "We hope that in the future the therapeutic approaches that we are developing may have utility in these cases."

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